Polyol composition

ABSTRACT

PCT No. PCT/EP97/01787 Sec. 371 Date Oct. 21, 1998 Sec. 102(e) Date Oct. 21, 1998 PCT Filed Apr. 10, 1997 PCT Pub. No. WO97/39739 PCT Pub. Date Oct. 30, 1997A polyol composition useful for the production of tablets for consumption. The polyol is obtained by co-spray drying or co-fluidized bed granulating at least two polyols, one of which is a non-hygroscopic polyol, and the non-hygroscopic polyol is present in an amount of at least 80% by weight. An optional binder may be present. An active medicament may be present.

This Application is a 371 of PCT/EP97/01787 filed Apr. 10, 1997.

The invention relates to a composition obtainable by co-spray-drying orco-fluidized-bed granulation essentially consisting of at least twopolyols and, if appropriate, a binder, having a content of at least onenon-hygroscopic polyol of more than 80% by weight, and to its use as atableting aid.

Polyols and polyol mixtures are used to a great extent as noncariogenicadditives and carriers, inter alia for pharmaceutical active compounds,tablets to be chewed and sucked, and other products of thepharmaceutical and confectionery industries. Polyols are generallyproduced by hydrogenation of their underlying sugars. In solid form,they can be obtained both by crystallization and by spray-drying.

The particular advantage of some polyols is that they are also suitablefor direct pressing without further aids and additives.

Non-hygroscopic polyols are those polyols which, at a relative humidityof 80%, absorb less than 5% water at room temperature in the course of 7days.

The known polyols, mannitol, lactitol, isomaltitol, xylitol, have lowhygroscopicity of this type, but exhibit poor tableting behaviour (lowtablet hardness, crusting, high abrasion). Achieving high tablethardnesses is fundamentally advantageous, since carriers are frequentlyused only in small amounts in pharmaceutical formulations and activecompounds can drastically decrease the tablet hardnesses, so that adesired formulation cannot be tableted.

Whereas lactitol, isomaltitol and xylitol are rarely used in theproduction of compressed articles, mannitol is widely used inpharmaceutical formulations.

However, the use of mannitol represents an increase in the amount ofwork, since it must generally be granulated wet prior to compressionwith the remaining formula constituents. Directly tabletable mannitol isalso commercially available, but, in comparison with sorbitol, it canachieve only unsatisfactory tablet hardnesses.

Using sorbitol, in particular in the case of spray-drying, very goodtablet hardnesses are achieved with correspondingly smooth surface ofthe compressed articles. However, the hygroscopicity of sorbitol isconsiderably higher than that of the other polyols, which restricts itsapplicability.

DE 32 45 170 proposes preparing a polyol combination of sorbitol and10-15% by weight of mannitol by spray-drying. This is intended toincrease the flexural strength of the tablets. However, thehygroscopicity remains essentially unchanged. There is no indicationthere that polyol combinations which were prepared by spray-drying andhave mannitol as principle component can achieve improved properties, inparticular high binding capacity for active compounds at lowerhygroscopicity.

EP 0 528 604 describes a sorbitol and xylitol composition obtainable byco-melting. However, this leads to tablets having a comparatively lowhardness.

The object was therefore to provide a polyol composition which can beprepared without problems and whose tableting properties, in particularwith regard to tablet hardness and binding capacity, are improved incomparison with known polyols.

It has now been found that a polyol composition obtainable byco-spray-drying comprising at least 80% by weight of one or morenon-hygroscopic polyols, on tableting at the same compression pressure,on the one hand gives higher tablet hardnesses and a much smoothersurface, and on the other hand has a markedly lower hygroscopicity incomparison with sorbitol.

The invention thus relates to a composition essentially consisting of atleast two polyols obtainable by co-spray-drying, which compositioncomprises at least 80% by weight of at least one non-hygroscopic polyol,in particular mannitol.

The term polyol means sugar alcohols of the general formula

    CH.sub.2 OH--(CHOH).sub.n --CH.sub.2 OH,

where n is 2 to 6, preferably 3 to 4,

and their dimeric anhydrides, in particular C₁₂ H₂₄ O₁₁.

In particular, the term polyols means hexitols, such as sorbitol andmannitol, pentitols, such as xylitol, however, other possibilities arealso C₄ polyalcohols, such as erythritol, or C₁₂ polyalcohols, such aslactitol. The term polyol composition means a composition of a pluralityof polyols which differ markedly in their composition from compositionsarising in the industrial production of mannitol, preferably thosecompositions which comprise at least two polyols having a differentnumber of carbon atoms, in particular the term means a compositioncomprising mannitol and at least one other hexitol, in particularsorbitol or a dodecaitol, in particular lactitol.

Preferred embodiments are

a) a composition obtainable by dissolving at least two polyols in waterand spraying the resulting aqueous mixture in an air stream at atemperature from 120 to 300° C.

b) a composition obtainable by dissolving at least two polyols in waterand vortexing the resulting mixture in an air stream at a temperaturebetween 40° and 110° C.

c) a composition where mannitol and sorbitol, mannitol and lactitol ormannitol, sorbitol and lactitol and other polyols, in particularmannitol, sorbitol and lactitol, are used as polyols.

d) a composition where the ratio of mannitol to sorbitol/lactitol is ina range between 80:20 and 99:1, in particular between 90:10 and 98:2. Ina particularly preferred embodiment, the ratio is about 95:5, inparticular the ratio mannitol:sorbitol:lactitol is in a range from90:1:9 or 90:9:1 to 98:1:1.

e) a composition according to one of the preceding claims, characterizedin that [sic] the water content is less than 1% by weight.

f) a composition which comprises from 0.05 to 5% by weight of a binder.

g) a composition which has filaments, preferably needle-shapedfilaments, whose length/width ratio is between 15 and 5 to 1, in acrystal structure.

The invention further relates to compressed articles comprising acomposition according to the invention.

The invention further relates to a process for preparing a compositionessentially consisting of at least two polyols and, if appropriate, abinder, comprising the following steps:

a) preparing an aqueous solution of at least two polyols, the solutioncomprising more than 80% of one or more non-hygroscopic polyols, basedon the total polyol content,

b1) spraying the resulting solution in an air stream at a temperaturebetween 120 and 300° C., the water being evaporated, or

b2) vortexing the resulting solution in an air stream at a temperaturebetween 40 and 110° C., the water being evaporated.

In a particularly preferred embodiment, the polyol composition accordingto the invention essentially consists of 85 to 99% by weight, inparticular 88 to 98% by weight, of mannitol and 5 to 15% by weight, inparticular 6 to 12% by weight, on one or two polyols selected fromlactitol and sorbitol.

Preferably, the polyol composition according to the invention comprisesmore than 90% by weight, and less than 99% by weight, of mannitol.

For the spray-drying, an aqueous solution of at least two polyols isused. The solids content is set in advance to about 30 to about 75% byweight, in particular 50 to 72% by weight, preferably by mixing, at atemperature of 80° C., two or more polyol solutions in the desiredratio. The spraying is performed by atomizing using nozzles, preferablyusing a centrifugal atomizer, into a dry, centrifugally injected airstream heated to a temperature of 120-300° C., preferably 140-190° C.The amount of the polyol solution supplied is matched to that of theinjected hot air in such a manner that the polyol is dried to a watercontent of about 0.3 to about 1% by weight. In any case, the watercontent should be below 1% by weight.

The fluidized-bed granulation is carried out as described, for example,in P. Grassmann, F. Widmer "Einfuhrung in die thermischeVerfahrenstechnik" [Introduction to Thermal Process Engineering], VerlagDeGruyter, Berlin 1974.

The polyol agglomerates which are obtained here by dehydrating thepolyol solution droplets are heated in the spray-drying to a temperatureof about 50 to about 70° C., while the injected air is cooled to aboutthe same temperature. The polyol composition is collected in vessels andis, after cooling, directly suitable for producing tablets, compressedarticles or chewing gum.

The polyols thus obtained, on account of their filamentousmicrostructure, have a binding capacity for active compounds which isfar higher than that of crystalline mannitol and which corresponds tothat of pure sorbitol, but without exhibiting its disadvantageoushygroscopicity.

The polyol composition thus characterized has a number of advantageoustableting properties:

Surprisingly, it can be observed that using the polyol compositionaccording to the invention, at the same compression force, hardertablets having a markedly smoother surface can be produced than usingthe known mannitol quality grades, including the known TLC mannitoltypes and mechanical polyol triturations. The tablet hardnessessentially determines the sucking properties. Using a polyolcomposition according to the invention, optimally smooth, hard tabletscan be produced even at very low compression forces. Tableting machinesby means of which the polyol composition according to the invention iscompressed can therefore operate at relatively low compression forcesand are subject in this manner to lower wear.

Owing to the filamentous structure, the polyol composition according tothe invention is able to bind even relatively large amounts ofadditives, such as pharmaceutical active compounds, dyes or otheradmixtures. Even at a high loading with additives, homogeneous mixturesare obtained, and the compressed articles produced therefrom have auniform appearance.

On account of the special type of production by spraying an aqueoussolution, it is possible to distribute water-insoluble and water-solubleadmixtures, such as citric acid, sweeteners, in particular acesulfame-K,Aspartam®, saccharin, cyclamate and sucralose, neohesperidin DC, dyesand pharmaceutical active compounds, preferably vitamins, in particularascorbic acid and the like, homogeneously in the polyol composition orthe tablets produced therefrom.

The binders to be added if appropriate are familiar to those skilled inthe art and serve to increase the strength of the composition. Binderswhich are preferred are cellulose derivatives, in particularhydroxypropylemethylcellulose, carboxymethylcellulose or starch.

In addition to the polyol composition according to the invention, thecompressed articles according to the invention comprise one or moreconstituents selected from the group consisting of: pharmaceuticalactive compounds and substances permitted by food legislation. Preferredsubstances permitted by food legislation are natural, nature-identicalor synthetic aromas or flavourings, vitamins, trace elements, minerals,dyes, lubricants, release agents, sweeteners, stabilizers orantioxidants. The content of these constituents is preferably between0.01 and 80%, in particular between 0.1 and 30%.

These compressed articles are produced in a manner known per se bymixing the constituents in dry form and then tableting them.

PREPARATION EXAMPLES Example 1

A 50% aqueous solution which comprises, based on the dry mass, 95 partsof mannitol, 1.5 parts of hydroxyproplymethylcellulose and 3.5 parts ofsorbitol is prepared.

This polyol solution is sprayed by means of a centrifugal atomizer atabout 50° C. into the upper part of a cylindrical stainless steel tower.At the same time, air heated to about 160° C. and polyol granules areinjected tangentially into the spraying zone. The solids stream is takenoff via a cooling drum and then divided: One part is returned to thespraying zone of the tower and the remainder is screened, dried furtheron a fluidized bed and then packaged. The resulting product can becompressed without problems and leads to tablets having a very smoothsurface.

Example 2

A 50% aqueous solution which, based on the dry mass, comprises 90.5parts of mannitol and 9.5 parts of sorbitol, is prepared. The productobtained by spray-drying in a similar manner to Example 1 can becompressed without problems, results similar to those described inExample 1 being achieved.

Example 3

A 50% aqueous solution which comprises, based on the dry mass, 95 partsof mannitol and 5 parts of sorbitol, is prepared. The product obtainedby spray-drying in a similar manner to Example 1 may be compressedwithout problems, results similar to those described in Example 1 beingachieved.

Example 4

A 50% aqueous solution which comprises, based on the dry mass, 95 partsof mannitol and 5 parts of lactitol, is prepared. The product obtainedby spray-drying in a similar manner to Example 1 may be compressedwithout problems, results similar to those described in Example 1 beingachieved.

Scanning electron micrographs recorded using a Jeol 630 F scanningelectron microscope at 50x and 5000x enlargement of the polyolcompositions according to Examples 2 and 4, of commerically availableTLC mannitol, of a mechanical trituration of 90.5% mannitol and 9.5%sorbitol and of a mechanical trituration of 90% mannitol and 10%lactitol were assesed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a 50× enlargement of a mannitol/sorbitol preparationobtainable in accordance with Example 2.

FIG. 1b shows a 5000× enlargement of a mannitol/sorbitol preparationobtainable in accordance with Example 2.

FIG. 2a shows a 50× enlargement of a mannitol/lactitol preparationobtainable in accordance with Example 4.

FIG. 2b shows a 5000× enlargement of a mannitol/lactitol preparationobtainable in accordance with Example 4.

FIG. 3a shows a 50× enlargement of a commercially available TLC mannitol(Pearlitol 300).

FIG. 3b shows a 5000× enlargement of a commercially available TLCmannitol (Pearlitol 300).

FIG. 4a shows a 50× enlargement of a mechanical trituration of 90.5%mannitol and 9.5% sorbitol.

FIG. 4b shows a 5000× enlargement of a mechanical trituration of 90.5%mannitol and 9.5% sorbitol.

FIG. 5a shows a 50× enlargement of a mechanical trituration of 90%mannitol and 10% lactitol.

FIG. 5b shows a 5000× enlargement of a mechanical trituration of 90%mannitol and 10% lactitol.

The micrographs of the Example 2 and 4 compositions clearly show thatthe preparations according to the invention are agglomerates ofextremely fine needle-shaped crystallites, whereas, in contrast, theagglomerates of TLC mannitol consist, in a significantly differentiablemanner, of relatively large crystallites.

The micrographs of the mechanical mixtures show both agglomerate types.

Example 5 Tablets for sucking

    ______________________________________                                        Polyol composition prepared                                                                        491.0 parts by weight                                    in accordance with Example                                                    2 with addition of 0.8% by                                                    weight of citric acid,                                                        based on polyol used.                                                         Dry aroma of fruits                                                           (various flavour notes)                                                                             1.5 parts by weight                                     Magnesium stearate    2.5 partS by weight                                     ______________________________________                                    

The constituents are mixed and compressed at a compression pressure of30 kN to give tablets of 13 mm diameter and 500 mg weight.

Example 6 Vitamin C tablets

    ______________________________________                                        Ascorbic acid         105.0 parts by weight                                   Orange aroma          10.0 parts by weight                                    Polyol composition prepared                                                                        1377.5 parts by weight                                   in accordance with Example 2                                                  Magnesium stearate     7.5 parts by weight                                    ______________________________________                                    

The constituents are mixed and compressed at a compression pressure of11 kN to give tablets of 18 mm diameter and 1500 mg weight.

Example 7 Caffeine tablets

    ______________________________________                                        Polyol composition 462.5 parts by weight                                      according to Example 1                                                        Coffee aroma        25.0 parts by weight                                      Caffeine            10.0 parts by weight                                      Magnesium stearate  2.5 parts by weight                                       ______________________________________                                    

The constituents are mixed and compressed at a compression pressure of30 kN to give tablets of 13 mm diameter and 500 mg weight.

Example 8 Study of tableting properties

Tablets are prepared using various polyols:

    ______________________________________                                        Tablet diameter:                                                                        11 mm       Tablet weight:                                                                              450 mg                                    Tablet height:                                                                          3.7 to 3.9 mm                                                                             Compression pressure:                                                                        15 kN                                    ______________________________________                                    

Polyol used

A: Spray-dried mannitol:sorbitol=90.5:9.5 from Example 2

B: Spray-dried mannitol:sorbitol=95:5 from Example 3

C: Spray-dried mannitol:lactitol=95:5 from Example 4

D: Commercially conventional TLC mannitol

E: Crystallized mannitol

F: Mechanical trituration of mannitol with sorbitol in a ratio of 95:5

G: Mechanical trituration of mannitol with lactitol in a ratio of 95:5

H: Sorbitol, Instant Pharma, obtainable from Merck KGaA, Darmstadt.

The tableting properties of these products can be taken from Table I.

                  TABLE I                                                         ______________________________________                                        Polyol   A      B      C    D    E    F    G    H                             ______________________________________                                        Tablet   281    229    195  85   72   85   80   215                           hardness (kN)                                                                 Abrasion (%)                                                                           0.14   0.2    0.16 0.3  5.9  1.2  2.0  0.18                          ______________________________________                                    

The tablets according to the invention, on account of their hardness andtheir low abrasion, have more pleasant sucking properties than thecomparison samples (mannitol).

Example 9

Study of the hygroscopicity of the polyols

The polyols B, C, D, E, F, H from Example 8 are stored for 7 days at anatmospheric humidity of 76%.

The water absorption of the products can be taken from Table II

                  TABLE II                                                        ______________________________________                                        Polyol      B     C        D   E       F   H                                  ______________________________________                                        Water       1.8   0.44     0.4 0.05    1.9 5.3                                absorption (%)                                                                ______________________________________                                    

The polyol mixtures prepared according to the invention show, incomparison with commercially available TLC mannitol (D), a slightlyhigher hygroscopicity, but this is markedly reduced in comparison withsorbitol (H).

Example 10

Study of the loading capacity (ordered stable mixtures) of the polyols.

Polyols B and D are sieved through a sieve having a pore size of 200 μmand mixed with 3% by weight of a pharmaceutical active compound having aparticle size of less than 40 μm.

The mixture thus obtained is briefly subjected to air discharge over anair-jet sieve of 100 μm. The active compound remaining in the mixture isdetermined colorimetrically.

The loading capacity of the carrier material thus determined (recoveryrate in %) can be taken from Table III.

    ______________________________________                                        Polyol       B            D     H                                             ______________________________________                                        Capacity (at 3%)                                                                           83           72    83                                            ______________________________________                                    

The loading capacity is markedly improved in comparison with TLCmannitol.

Example 11

Comparison between the tabletting behaviour of polyol compositions andcommercially available TLC-mannitol

The test material corresponds to the composition prepared according toExample 3 (95 parts of mannitol, 5 parts of sorbitol), which is mixedwith 1% of magnesium stearate based on the total weight and pressed toform tablets. In comparison, the same weight ratios are trituratedtogether. In addition, corresponding compositions are studied which wereprepared by co-spray-drying of 60 parts of mannitol with 40 parts ofsorbitol or by triturating together corresponding weight ratios ofmannitol and sorbitol and were then mixed with 1% of magnesium stearate,based on the total mass.

    ______________________________________                                        Tabletting press                                                                           Korsch EK 0                                                      Tablet diameter                                                                            11 mm                                                            Pressing tools                                                                             flat, faceted with breaking notch                                Tablet weight                                                                              500 mg                                                           Fracture strength tester                                                                   Erweka TBH 28 (converted to Schleuniger)                         Abrasion test                                                                              Erweka Friabilator TA                                            ______________________________________                                    

The tablets prepared were subjected to an X-ray structural analysis anda DSC analysis.

The X-ray diffraction analysis was performed with a Siemens D5000 powderdiffractometer.

Sample preparation:

Approximately 0.5 g of the sample is lightly ground in an agate mortar,applied to a Mylar film and covered with a second Mylar film. The Mylarfilm was fixed to a sample holder suitable for the diffractometer.

Measurement conditions:

Transmission mode, generator power 40 kV/30 mA, Cu-Kα1-radiation(primary monochromator), positionally sensitive detector (3.3 kV),measuring range: 5°-80° (2θ); step time: 24 s; step size; 0.05°.

Procedure:

The measurement is begun immediately after sampling. The X-raydiffractogram recorded is compared with the reference diffractograms.

DSC analysis (Differential Scanning Calorimetry) was performed using acell (System 2100) with a central computer, module interface, DSCcellbase and DSC cell from TA Instruments (previously Du Pont).

    ______________________________________                                        Measurement conditions                                                        ______________________________________                                        Sample vessel       standard open cup                                         Atmosphere          0.15 1/min N.sub.2                                        Temperature calibration                                                                           o-terphenyl (T = 55.1° C.)                                             anisic acid (T = 183.2° C.)                        Heating rate        2° C./min                                          Sample vessel starting temperature                                                                room temperature                                          ______________________________________                                    

The DSC measurement is performed from room temperature up to 180° C.

The DSC curve is evaluated between 50 and 175° C. using the programme"General 4.1" and the heating rate is reported in °C./min.

FIGS. 1-9 each relate to the following:

FIG. 1

Mannitol:sorbitol 95:5, triturated

X-ray structural analysis: CT: 24.0 s, SS: 0.050 dg, WL: 1.5406

FIG. 2

Mannitol:sorbitol 95:5, co-sprayed

X-ray structural analysis: CT: 24.0 s, SS: 0.050 dg, WL: 1.5406 A

FIG.: 3

Mannitol:sorbitol 95:5, co-sprayed

X-ray structural analysis: CT: 24.0 s, SS: 0.050 dg, WL: 1.5406 A

FIG.: 4

Mannitol:sorbitol 60:40, triturated

X-ray structural analysis: CT: 24.0 s, SS: 0.050 dg, WL: 1.5406 A

FIG.: 5

Mannitol:sorbitol 60:40, co-sprayed

X-ray structural analysis: CT: 24.0 s, SS: 0.050 dg, WL: 1.5406 A

FIG.: 6

Mannitol:sorbitol 60:40, triturated DSC analysis

FIG.: 7

Mannitol:sorbitol 60:40, co-sprayed DSC analysis

FIG.: 8

Comparison between the tabletting behaviour of polyol combinations andcommercially available TLC-mannitol abrasion

FIG.: 9

Comparison between the tabletting behaviour of polyol combinations andcommercially available TLC-mannitol: Tablet Hardness

What is claimed is:
 1. A process for the preparation of a compositionconsisting essentially of at least two polyols comprising the followingsteps:a) preparing an aqueous solution of at least two polyols, thesolution comprising more than 80% of one or more non-hygroscopic polyolsbased on the total polyol content, and b) spraying the resultingsolution in an air stream at a temperature between 120 and 300 C., thewater being evaporated, whereby the composition thus prepared contains afilamentous microstructure.
 2. A process as claimed in claim 1, furthercomprising including a binder.
 3. A process as claimed in claim 1,wherein the non-hygroscopic polyol is selected from the group consistingof mannitol, sorbitol, lactitol, isomaltitol, xylitol and erythritol. 4.A process as claimed in claim 1, wherein the polyols are mannitol andsorbitol, mannitol and lactitol, or mannitol, sorbitol, and lactitol. 5.A process as claimed in claim 4, wherein, the ratio of mannitol tosorbitol/lactitol is in a range between 80:20 and 99:1.
 6. A process asclaimed in claim 4, wherein the ratio of mannitol:sorbitol; lactitol isin a range between 90:1:9 or 90:9:1 and 98:1:1.
 7. A process as claimedin claim 1, wherein the water content of the resulting composition isless than 1% by weight.
 8. A process as claimed in claim 2, wherein thebinder is present in an amount of from 0.05 to 5% by weight of binder.9. A process as claimed in claim 4, wherein the polyols are mannitol,sorbitol, and lactitol.
 10. A process as claimed in claim 9, furthercontaining polyols other than mannitol, sorbitol, and lactitol.
 11. Aprocess as claimed in claim 4, wherein the ratio of mannitol tosorbitol/lactitol is in a range between 90:10 and 98:2.